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Before tearing through the world, causing millions of deaths and upending life as we knew it, SARS-CoV-2 had to somehow make the jump from an animal host to humans — but how?

Though the exact pathway the virus took is hotly debated, heartburn doxycycline data suggests that the original reservoir for the precursor virus to SARS-CoV-2 was likely bats. 

“It’s reasonable to believe that SARS-CoV-2 originated ultimately from bats because so many related viruses do circulate in bats,” especially coronaviruses, said Dr. Amesh Adalja, an infectious diseases specialist and a senior scholar at the Johns Hopkins Center for Health Security in Baltimore. The related coronaviruses that previously caused epidemics, MERS-CoV and SARS-CoV, both evolved in bats and hopped over to humans through an intermediate species (camels in the case of MERS and civets in the case of SARS). 

At the start of the pandemic, researchers at the Wuhan Institute of Virology posted the genome of another strain of coronavirus (RaTG13) that was previously found in horseshoe bats (Rhinolophus affinis), according to Nature.  The genome of RaTG13 is 96% identical to that of SARS-CoV-2, and is still the most closely related coronavirus found to date.

But a 4% difference in genome means that it’s been around 50 years since they last shared a common ancestor, which, in turn, suggests that there could still be an intermediate species involved, according to Nature. 

Some of those differences are in key spots of the genome. For instance, the genes that code for the virus’ spike protein, which the virus uses to bind to human cells — specifically the receptor binding domain, the location where the virus latches on to human cells — differ between RaTG13 and SARS-CoV-2, Adalja told Live Science. These critical differences explain “why SARS-CoV-2 is the virus that found its way into humans and caused the pandemic, and not RaTG13, Adalja said 

The next-closest bat coronavirus (RmYN02) has a genome that’s 93.3% similar to that of SARS-CoV-2, according to a study published June 2020 in the journal Current Biology. Related coronaviruses were also found in Shamel’s horseshoe bats (Rhinolophus shameli) that were sampled in Cambodia in 2010 and were recently analyzed, according to a World Health Organization (WHO) report on the origins of the coronavirus that was published in February 2021. The genomes of these coronaviruses (RshSTT200 and RshSTT182) were 92.6% similar to that of SARS-CoV-2.

“The results suggest that the geographical distribution of SARS-CoV-2 related viruses is much wider than previously expected,” according to the WHO report. 

A closer look 

Scientists don’t yet know where, how and when SARS-CoV-2 evolved the changes needed to infect human cells. This process could have occurred in bats, or the virus could have hopped from bats to another species, such as pangolins, and further evolved there.

One study suggests that over a century ago, one  lineage of coronavirus circulating in bats gave rise to SARS-CoV-2, RaTG13 and a Pangolin coronavirus known as Pangolin-2019, Live Science previously reported. The ancestor to the Pangolin-2019 virus likely diverged at that time from the other two; then in the 1960s or 1970s, this lineage once again split into two, creating the ancestor of RaTG13 and the ancestor of SARS-CoV-2. 

Another more recent study published in the journal Cell found that a single mutation may have given the coronavirus the ability to infect human cells, but it’s not clear when or in what animal the virus would have acquired this mutation, Science News reported.

Scientists found that pangolin coronaviruses have between 85.5% and 92.4% genomic similarity to SARS-CoV-2, according to another study published in Nature in March 2020. That raises the possibility that pangolins may have been the intermediate host for SARS-CoV-2.

“Evidence from surveys and targeted studies so far have found most highly related viruses in bats and pangolins, suggesting they may be the reservoir of SARS-CoV-2,” according to the WHO report. But “viruses identified so far from neither bats nor pangolins are sufficiently similar to SARS-CoV-2 to serve as the direct progenitor of SARS-CoV-2.”

Minks and cats are also highly susceptible to infection with SARS-CoV-2, which suggests that such animals may also serve as “potential reservoirs,” according to the WHO report. 

But surveys to look for such viruses in potential reservoir species are not conducted systematically, and  “potential reservoir hosts are massively under-sampled,” according to the report. In other words, the potential spillover host could be sitting right under our noses, and we just haven’t tested enough to find it yet.

“It is a possibility that there may be an animal that’s not been thought of” that served as the intermediate host for the novel coronavirus, Adalja said.

It’s not easy to tease apart the origin of SARS-CoV-2, or any virus that spills over to humans. “When this virus jumped into humans it didn’t announce it to the world,” Adalja said. The virus is thought to have been first circulating in China in the Fall of 2019, which is also the start of the flu season. It’s likely that the earliest cases of COVID-19 were assumed to be flu cases, meaning COVID-19 wasn’t diagnosed until the coronavirus became more widespread, he said. What’s more, “The Chinese government has not been transparent about those early days of the pandemic and has not allowed access to a lot of research that was going on,” he added. 

“Because nobody has identified a virus that’s 100% identical to SARS-CoV-2 in any animal, there is still room for researchers to ask about other possibilities,” Arinjay Banerjee, a virologist at the Vaccine and Infectious Disease Organization in Saskatchewan, Canada, told The Associated Press. One of those possibilities is the “lab leak theory,” which suggests that the virus didn’t hop from animals to humans out in the world but accidentally spilled over from a sample to workers in a lab. 

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“I think it is a possibility,” Adalja said. “We know that there were labs that were working with coronaviruses very similar, including RaTG13, and we know that biosafety concerns exist in all labs.” This possibility needs to be fully investigated, and the Chinese government needs to be transparent, he added. 

Still, with the current data, most experts support the hypothesis that SARS-CoV-2 spilled over from animals out in the world, he said. Figuring out the origin will be important, in order to be better prepared for the next pandemic, he said. For example, if the virus did hop to humans from an intermediary animal, knowing which animal may help us reduce human interactions with it, he added. 

“This is not the last coronavirus emergency that we’re going to face,” Adalja said. “Understanding and unraveling the early days of the SARS-CoV-2 pandemic is going to be really important to help us become more resilient to the next pandemic and to be much better prepared for emerging infectious diseases and zoonotic infections in the future.”

Originally published on Live Science.

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